P6285Protective effects of exercise on vascular function are mediated by NADPH oxidase 4

Abstract Background/Introduction Physical activity is one of the most potent strategies to prevent endothelial dysfunction. Recent evidence indicates vaso-protective properties of H2O2 produced by main endothelial NADPH oxidase isoform 4 (Nox4) in the vasculature. Purpose Therefore, we hypothesized that Nox4 connects physical activity with vaso-protective effects. Methods and results Analysis of endothelial function by Mulvany myograph showed endothelial dysfunction in wild-type as well as in Nox4−/− mice after 20 weeks on high-fat diet. Access to voluntary running wheels during high-fat diet prevented endothelial dysfunction in wild-type but not in Nox4−/− mice. Mechanistically, exercise led to increased H2O2 release in the aorta of wild-type mice with increased phosphorylation of eNOS pathway member AKT serine/threonine kinase 1 (Akt1), subsequently. Both effects were diminished in aortas of Nox4−/− mice. Deletion of Nox4 also led to decreased capacity for intracellular calcium release and reduced phenylephrine-mediated contraction, whereas potassium-induced contraction was unaffected. H2O2 scavenger catalase reduced phenylephrine-contraction in wild-type mice. Supplementation of H2O2 increased phenylephrine-induced contraction in Nox4−/− mice. Exercise induced key regulator of mitochondria biogenesis peroxisome proliferative activated receptor gamma, coactivator 1 alpha (Ppargc1a) in wild-type but not Nox4−/− mice. Furthermore, exercise induced citrate synthase activity and reduced mitochondria mass in the absence of Nox4. Thus, Nox4−/− mice became less active and ran less compared with wild-type mice. Conclusions Nox4 derived H2O2 plays a key role in exercise-induced adaptations of eNOS and Ppargc1a pathway and intracellular calcium release. Hence, loss of Nox4 diminished physical activity performance and vascular protective effects of exercise. Acknowledgement/Funding This work was supported by a research grant of the German Cardiac Society (DGK) (to H.L.) and DFG (Grant MO 1695/4-1 to H.M.).